Ransom was the third of four children of a Methodist minister. His family was highly literate. As a child, he read his family's library and engaged his father in passionate discussions. He wrote many books and poems in his life.

Ransom was home schooled until age ten, and entered Vanderbilt University at fifteen, graduating first in his class in 1909. He interrupted his studies for two years to teach sixth and seventh grades in Taylorsville, Mississippi and Latin and Greek in Lewisburg, Tennessee.

After teaching one more year in Lewisburg, Ransom was selected as a Rhodes Scholar. He attended Oxford University's Christ Church, 1910-13, where he read "Greats", as the course in Greek and Latin classics is called.

After one year teaching Latin in the Hotchkiss School, Ransom was appointed to the English department at Vanderbilt University in 1914. During the First World War, he served as an artillery officer in France. After the war, he returned to Vanderbilt. In 1920, he married Robb Reavill; they raised three children.

In 1937, Ransom accepted a position at Kenyon College in Ohio. He was the founding editor of the Kenyon Review, and continued as editor until his retirement in 1959.

Ransom has few peers among 20th century American university teachers of humanities; his distinguished students include Donald Davidson, Randall Jarrell, Robert Lowell, Andrew Lytle, Allen Tate, Peter Taylor, Robie Macauley, Robert Penn Warren, E.L. Doctorow, Cleanth Brooks, and Richard M. Weaver.

At Vanderbilt, Ransom was a founding member of the Fugitives, a literary group that included Donald Davidson, Allen Tate, and Robert Penn Warren. Under their influence, Ransom, whose first interest had been philosophy, specifically John Dewey and American pragmatism, began writing poetry. His first volume of poems, Poems about God (1919), was praised by Robert Frost and Robert Graves. Ransom later declined to republish these poems, deeming them unrepresentative of his work.

His literary reputation is based chiefly on two collections of poetry, Chills and Fever (1924) and Two Gentlemen in Bonds (1927). Believing he had no new themes upon which to write, his subsequent poetic activity consisted almost entirely of revising ("tinkering", he called it) his earlier poems. Hence Ransom's reputations as a poet is based on the fewer than 160 poems he wrote and published between 1916 and 1927. Despite the brevity of his poetic career and output, he won the Bollingen Prize for Poetry in 1951. His 1963 Selected Poems received the National Book Award the following year.

Ransom primarily wrote short poems examining the ironic and unsentimental nature of life, with domestic life being a major theme. Arguably Nashville's greatest author, he was also an Agrarian, and Southern poet. An example of his Southern style is his poem "Janet Waking", which "...mixes modernist with old-fashioned country rhetoric" (Tillinghast 1997).

To highlight the incongruity between a steady rhythm of words and the unsteady moments that make up human existence, Ransom often employed regular meter of the sort once common in the English language tradition, and which he altered as needed to fit the flow of his poems. For example, in his poem "Blue Girls", the meter halts the lines to produce a pause at certain moments and to add emphasis. He also occasionally employed archaic diction.

Tillinghast (1997) called Ransom a "major minor poet". A major poet could be expected to labor over great works reminding the audience of his grandeur through sestinas, epic, or a philosophical discovery, whereas a minor poet does not carry such high expectations, and is free to explore simpler subjects purely because they delight him. Ransom knew his poems were minor, and used the opportunity to explore domestic themes and Southern life. Being a minor poet also allowed him to make ironic use of simple diction, playing on the intellectual connotations of words.

more or less founded the school of literary criticism known as the New Criticism, which gained its name from his 1941 volume of essays The New Criticism. This school, which dominated American literary thought throughout the middle 20th century, emphasized close reading, and criticism based on the texts themselves rather than on extraneous information. Ransom had argued for more "precise and systematic" analysis of texts in a 1937 essay, " Criticism, Inc." He was critical of several aspects of the movement, however, as well as of poet T. S. Eliot, who became a favorite of other New Critics. Ransom remained an active essayist until his death. A collection of his essays first published in the Kenyon Review was published in 1972. Ransom served as a Senior Fellow of the Kenyon School of English and subsequently as a Senior Fellow of the Indiana School of Letters.

In 1930, Ransom along with 11 other Southern Agrarians published the Agrarian manifesto I'll Take My Stand: The South and the Agrarian Tradition, which bemoaned the tide of modernity that appeared to be sweeping away traditional Southern and American culture. Ransom at first defended the manifesto's assertion that the industrialization of modern society was a dehumanizing force, in various essays influenced by his Agrarian beliefs. In 1936, however, he expressed some doubts about the position. In 1945 publicly renounced it.

In 1937, Ransom moved his career from a Southern university very hospitable to the Southern tradition in letters and social philosophy, to a northern, albeit deeply rural, liberal arts college that was less so. Ransom's abandonment of Agrarianism was foreshadowed by one of his most famous essays, "God Without Thunder: An Unorthodox Defense of Orthodoxy" (1930). It was a philosophically informed defense of the stern, "inscrutable" God of the Old Testament as opposed to the permissive Jesus of the Gospels, there equated with modern science. Ransom's "traditionalist" assertions in this essay are overshadowed by its critique and rejection of the (American) religious offerings of his day.